Synthesis of glutamic acid and salts thereof



SYNTHESIS OF GLUTAMIC ACID AND SALTS THEREOF Leo J. Novak and Jack .1. Bulloif, Dayton, Ohio, assignors to The Commonwealth Engineering Company of Ohio, Dayton, Ohio, a corporation of Ohio No Drawing. Application June 7, 1954, Serial No. 435,096

4 Claims. (Cl. 260-533) This invention relates to an improved method for synthesizing glutamic acid and salts thereof.

Monosodium glutamate has attained wide commercial acceptance as a cooking aid since it has been found to enhance the natural flavor and taste of various foods without itself contributing any noticeable odor or taste to the food.

The monosodium salt having value for accenting food flavors is derived from the active levorotatory form of the acid. This latter substance occurs naturally in vegetable protein hydrolyzates from which it can be extracted. However, the selective extraction of'the l-glutamic acid is an expensive process and the cost of the extracted acid is, therefore, quite high.

Various organic syntheses of glutamic acid are known, including procedures utilizing, as starting materials, relatively expensive malonic acid derivatives such as aminomalonic esters, benzoylaminomalonic esters, aceto-aminomalonic ester and phthalimidomalonic ester. These processes are tedious and result in low yields of a racemic product, i. e., a mixture of d-and l-glutamic acid in which the l-glutamic acid is present in an amount of about 50%. To find a market for use as a flavor enhancing agent with the sodium salt of protein hydrolyzate extracts in which the active l-glutamic acid is not admixed with the inactive dextro-rotary form, the sodium salt derived from racemic glutarnic acid containing only about 50% by weight of the active levorotatory form, must sell at about half the price of the salt of the protein hydrolyzate extracts. This is not feasible economically since the cost of synthesizing the acid by the known methods is relatively high.

One object of the present invention is to provide a new and improved method of synthesizing glutamic acid utilizing comparatively inexpensive starting materials and reagents and involving a series of reactions which are readily controllable.

Another object is to provide a method of synthesizing sodium glutamate which can be profitably marketed at a price considerably less than that of the sodium salt of glutamic acid synthesized by the procedures heretofore available to the art.

These and other objects are achieved by utilizing, as starting material for the synthesis, cyclopentadiene obtained by depolymerization of readily available and inexpensive polymers of cyclopentadiene such as the dimer, dicyclopentadiene, which is easily depolymerized to the active monomer by distillation at atmospheric pressure.

In a preferred embodiment of the invention, the dicyclopentadiene is depolymerized to cyclopentadiene by distillation, the monomer is treated with gaseous hydrogen chloride or bromide to produce 2-chloroor 2-bromo cyclopentene-l, the cyclopentene-l is oxidized, with cleavage of the ring, to Z-chloroglutaric or 2-bromoglutaric acid which, on ammonolysis, yields ammonium glutamate, the latter being converted to glutamic acid hydrochloride which, on treatment with aqueous sodium hydroxide, yields a mixture of substantially equal proportions of the m mtes Patent 2 ,791,606 Patented May 7, 1957 sodium salts of the active l-glutam-ic acid and inactive d-glutamic acid.

In a modification of the procedure outlined, the 2'- ice chloroor 2 -bromo-cyclopentene-1 is converted directly to Z-amino-cyclopentene-l by treatment with an excess of an aqueous solution of ammonia, and the amino group is protected during oxidation and opening of the ring by intermediate acylation, whereby the two hydrogen atoms of the amino group are replaced by lower acyl (2-4 carbons) radicals. Oxidation of the diacyla'ted amino cyclopentene-l in the presence of sulfuric acid yields the corresponding diacylated glutamic acid which, on heating in the presence of the sulfuric acid, is converted to glutamic acid sulfate, the latter being in turn converted to the monosodium glutamate on treatment with aqueous sodium hydroxide. In this modified procedure oxidation of the diacylated amino cyclopentene-l and conversion of the resulting diacylated glutamic acid to the sulfate are preferably carried out in the same reaction vessel, without intermediate isolation of the oxidation product.

The following examples are given to illustrate the invention, it being understood that these examples are not intended to be limitative with respect to the specific details thereof.

Example I reflux-condenser. About 792 lbs. of the cyclopentadiene collected in the condenser are cooled in a tank and hydrogen chloride gas is bubbled through the cooled liquid at a temperature below 25 0., usually at 30 C. to 35 C., until 2-chlorocyclopentene-1 is produced. About 1128 lbs. of the latter are then treated with an excess of potassium permanganate and sulfuric acid, preferably introduced into the warmed solution concurrently and in the form of thin streams, with stirring of the mass. This oxidizing treatment opens the ring, with production of 2-chloroglutaric acid. About 1600 lbs. of the 2-chloroglutaric acid are autoclaved in 1300 lbs. of water containing 850 lbs. of ammonia and 1300 lbs. of CO2 at a temperature of 50 C. and under a pressure of 50 p. s. i. for 12 hours to produce 1300 lbs. of ammonium glutamate. The ammonium glutamate is treated with hydrochloric acid, the hydrochloride being formed, and an aqueous solution of sodium hydroxide is added to adjust the pH to the alkaline side and produce the desired sodium glutamate, which may be recovered from the solution by evaporation of the water, together with sodium chloride, the presence of which latter may be desirable in the condiment.

Instead of potassium permanganate, other similar oxidizing agents may be used, such as perrhenates, vanadates, chromates, ferrates or periodates. Instead of oxidizing the 2-halocyclopentene-1 in aqueous medium, a catalytic vapor phase process using air as the oxidant may be employed.

Other variations may be made in the procedure of Example 1. Thus, the 2-chloroglutaric acid may be aminated by autoclaving in from 1300 to 4250 lbs. of water at 35 C. to 65 C. and under a pressure of from 0 to 200 p. s. i. 'Also, for the amination, from 850 to 1250 lbs. of ammonia and from 1300 to 2640 lbs. of CO2 maybe used in the solution. The procedure described has the advantage that only a relatively small amount of ammonia is required to prevent the formation of polyalkylated by-products, i. e., only about 4 to 7 mole. The pH at which the amination is conducted under the conditions described prevents hydrolysis of the 2-chloroglutaric acid to 2-hydroxyglutaric acid and, in addition, under the described operating conditions, carbamate groups are formed which inhibit the formation of polyalkylated. mmQnil m. Salish hus. avoiding another, of the major disadvantages of prior syntheses.

Example 11 Example 111- About-1220 lbs. of 73%. dicyclopentadiene are charged intoa stillanddistilledas in Examplel. Hydrogen chloride gas. is bubbled. intov 792 lbs. of they cyclopentadiene recovered in. the. distillation until, 2,-chlorocyclopentene-l, is. produced. The 2-chlorocyclopentene-lis. converted directly to. the, 2-aminorcyclopenteneel by autoclaving, Ll. 2 8;.lb s. of, thechloro-derivative. with SOOOlbs. of 26% aqueousammonia for 8 hoursat 120. C. and 76 p. s. i. About 75L): lbs, of the 2 -amino -cyclopentene-l thus obtained are, acetylated by treatment. with excess acetyl chloride, and the diacetylated. product, 2 (diacetylamino) cyclopentene-l, is oxidized bytreatment with. potassium permanganate in the presence of. sulfuric acid, the oxidizing agent and catalystbeing introduced into the mass comprising the diacetylated material concurrently in the form of thin streams, with continuous stirring ofthe-mass to insure uniform distribution. of the permanganate and catalyst thercthrough. The mass is then heated for to lO minutes to effect conversion of the diacetyl glutamic acidresulting fromtheoxidation, to glutamic acid sulfate, after which sufi'icient aqueous sodium hydroxide is added toconvert the sulfate to sodium glutamate.

conditions may be varied; Thus, the Z-chlorocyclopentene-l' may. be autoclaved with an aminating solution consisting of from 5000-to 10,000 lbs. of 26%" to 30%aqueous ammonia for 8- to 12 hours at 120 C. to

170 C. and apressure of from70 to:200 p. s. i. Also, instead of oxidizing the diacetylamino-cyclopentene-l; by means of potassium permanganate in the presence of sulfuric acid, from 30% to- 60% nitric acid may beused asthe oxidizing agent, and the ammonium glutamate thus produced may be isolated, acidified with hydrochloric acid and-then treated-With aqueous sodium hydroxide to produce the monosodium glutamate.

Oxidizing acids other than: nitric acid may be used, such as perchloric, periodic or selenic' acid.

The sodium: glutamate (consisting ot'a mixture of substantially equal proportions: of the: 1- and d-forms) isobtained ingood yield as a white or almost white crystal-- line powder. whichmay-be add'ed'to meat. and other foodstuils to enhance the natural food flavor. The overallcostof: producing the sodium glutamate by the presentprocedure is comparatively low so that the product can lie-marketed at; a price competitive with the protein hydrolyzate extracts consisting. essentially of the active levorotatory form of the acid.

Instead of obtaining the cyclopentadiene by distillation of the dimer, other polymers of cyclopentadiene may be depolymerized to the monomer by distillation, such. as the, trimer, tetramer, etc.

it will be-undcrstood: that when it is desired to produce glutamic acid as such for any-purpose, as for. medicinal use; the free amino acid maybe obtained directly or recovered fromv the. salt by. neutralization of the latter. The hydrochloride; may'also' be used as. such, for instance 4; n, the. treatment. 0i achlcrhrdr a hypochlorhydria Likewise, when other alkali metal salts of glutamic acid are desired, these may be obtained by treating the hydrochloride with an aqueous solution of the appropriate alkali metal hydroxide, or alkaline earth metal hydroxide, such as potassium, lithium or calcium hydroxide.

It will also. be apparenttthat this invention. provides a novel method for producing-.Z-haloglutaric acids, 2-mouoacyl and Z-diacylamino-LS dicarboxylic acids, 2-monoacyliand 2-diacylaminocyclopentene-1.

Since the variations in. details mentioned herein, and others, may be made within the scope of the disclosure, and Without departing from. the; spirit and scope of the invention, it is to be understood that it is not intended to limit the invention except as defined in the appended claims.

What is claimed is:

. 1,, lira method for synthesizing glutamic acid and salts thereof, the steps, comprising distillinga polymer of cyclopentadiene-to obtainthc; monomer, treating the monomeric cyclopentadiene with a gaseous; hydrogen halide-selected frorrrdhe group consisting of: hydrogen chloride and hydrogenbromidez at a. temperature of from about 30 C. to --35 C., treating the resulting Z-halo-cyclopentene-l with an oxidizing; agent to; cleave. the ring and produce the; colt-responding Z-haloglut-aria acid, autocla-ving the: latter in. water, containing carbon dioxide and from: 4; to 7 mols; of; ammonia per molof the 2-haloglutaric acid: calculated; as. the. salt formed by reaction of the; canbon; dioxide; and ammonia, at a temperature between 35 C. and C. and a pressure-of-O-to 200-lbs./ sq. in. until ammonium. glutamate is-produced, treating the latter with hydrochloric acidv toconvert it to glutamic acidfhydrochloride, and: treating the hydrochloride with an; aquenussolution of a base selected from the group consisting ofi alkali metall and alkaline earth metal hydroxides to convert; the hydrochloride tothe alkali metal, respectively alkaline earth metal, glutamates.

2. The method: according to claim 1, characterized in that the oxidation agent used to cleave the ring of the Lhalo-cyclopentene-l and produce the Z-halo-glutaric acid: is potassium permanganate and the oxidation is carried out in the presence of sulfuric acid.

' 3. The method according toclaim 1, characterized in that the ammonolysis of the Z-halo-glutaric acid is carried out at about 50 C. and under apressure of about 5'0'lbsr/sq; in.

4; The method according to. claim 1, characterized in that the glutamic acid hydrochloride is treated with aqueous sodium hydroxide.

References Cited in thefile of this patent UNITED STATES PATENTS 2,085,784.- Bottoms July 6 1937 2,225,155; cheronis Dec. 17, 1940 2,323,861. Zellner July 6, 1943 2,390,597 Lawet a1, Dec. 1-1, 1945 2,438,484 Home Mar. 23,1948 2,549,456: Gresham eti-al. Apr. 17, 1951 OTHER REFERENCES Wilson .et al,: .Chem,.Reviews, vol. 34, pgs. 9-1.0 (1944), 1d,. Characterisation of; Organic. Compounds {1947), pas. 217-18. 

1. IN A METHOD FOR SYNTHESIZING GLUTAMIC ACID AND SALTS THEREOF, THE STEPS COMPRISING DISTILLINF A POLYMER OF CYCLOPENTADDIENE TO OBTAIN THE MONOMER, TREATING THE MONOMERIC CYCLOPENTADIENE WITH A GASEOUS HYDROGEN HALIDE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN CHLORIDE AND HYDROGEN BROMIDE AT A TEMPERATURE OF FROM ABOUT -30* C. TO -35*C., TREATING THE RESULTING 2-HALO-CYCLOPENTENE-1 WITH AN OXIDIZING AGENT TO CLEAVE THE RING AND PRODUCE THE CORRESPONDING 2-HALO-GLUTARIC ACID, AUTOCLAVING THE LATTER IN WATER CONTAINING CARBON DIOXIDE AND FROM 4 TO 7 MOLS OF AMMONIA PER MOL OF THE 2-HALOGLUTARIC ACID CALCULATED AS THE SALT FORMED BY REACTION OF THE CARBON DIOXIDE AND AMMONIA, AT A TEMPERATURE BETWEEN 35*C. AND 65*C. AND A PRESSURE OF 0 TO 200 LBS/SQ. IN. UNTIL AMMONIUM GLUTAMATE IS PRODUCED, TREATING THE LATTER WITH HYDROCHLORIC ACID TO CONVERT IT TO GLUTAMIC ACID HYDROCHLORIDE, AND TREATING THE HYDROCHLORIDE WITH AN AQUEOUS SOLUTION OF A BASE SELECTED FROM THE GROUP CONSISTING OF ALKALI METAL AND ALKALINE EARTH METAL HYDROXIDES TO CONVERT THE HYDROCHLORIDE TO THE ALKALI METAL, RESPECTIVELY ALKALINE EARTH METAL, GLUAMATES. 